In a standard vaccination programme, single dose vials containing substantially a single dose (e.g. 0.5 ml volume) of a given vaccine are used. Each vial is hermetically sealed on production, for example by a rubber stopper or septum which is inserted into an opening in the vial. The contents of the vial are accessed when required by puncturing the seal with a sterile injection device, such as a syringe, and withdrawing the contents into the injection device. In this manner, the contents remain sterile up to the point of injection into a subject. It is also known to use pre-filled syringes instead of single dose vials and associated injection devices.
The above approach is appropriate in most circumstances. However, where a rapid outbreak occurs (e.g. an influenza pandemic) and it is required to vaccinate a substantial proportion of a population, there might be insufficient manufacturing capacity to produce the requisite number of single dose vials. As an example, an influenza pandemic could affect millions, or even billions, of people.
This problem can be mitigated by the use of multidose vials. Vials containing more than a single dose of a drug product are known as multidose vials. Various such multidose vials are well known in the art. A typical example is illustrated in FIG. 1.
ISO 8362-1 specifies the form, dimensions and capacities of glass vials for injectable preparations. It also specifies the material from which such containers shall be made and the performance requirements of those containers. It applies to colourless or amber glass containers made from borosilicate or soda-lime glass, in the form of glass tubing, whether internally surface-treated or not, and intended for use in the packaging, storage or transportation of products intended for injection.
ISO 8362-4 specifies the shape, dimensions and capacities of glass vials for injectable preparations. It also specifies the material from which such containers shall be made and the performance requirements for the containers. It applies to colourless or amber glass containers moulded from borosilicate or soda-lime glass, with or without an internal surface treatment, and intended to be used in the packaging, storage or transportation of products intended for injection.
The multidose vial 10 comprises an outer shell 12 defining a main body portion 14 and a narrower neck portion 16. A tapering shoulder portion 18 connects the body and neck portions. The body, neck and shoulder portions together define an interior chamber 20 for containing multiple doses of a drug product. The chamber 20 might have a volume of about 6 ml, hence being sufficient to contain ten standard 0.5 ml doses of a vaccine (allowing for a standard 10% overfill allowance).
As best illustrated in FIG. 6, the neck portion 16 includes a lip 22 and defines an opening into the chamber 20. A cap 24 includes a plug portion 26, typically of rubber, that fills at least a portion of the interior space defined by the neck portion 16. The cap further includes a skirt 28, typically of aluminium, that enshrouds the lip 22. The cap 24 hence hermetically seals the opening. A flip-off disc (not shown), typically of a plastic material, overlies the upper surface of the cap 24, hence preventing contamination of the plug portion 26 prior to use.
ISO 8632-2 specifies the design, dimensions, material, performance, requirements and tests for single-use closures for injection vials covered by ISO 8362-1 and ISO 8362-4.
ISO 8632-3, ISO 8632-6 and ISO 8632-7 respectively specify details for aluminium caps for injection vials, caps made of aluminium-plastics combinations for injection vials, and injection caps made of aluminium-plastics combinations without overlapping plastics part.
It will be appreciated, however, that the multidose vial may take any suitable shape, and that the opening may be sealed in any suitable manner.
A problem associated with multidose vials is that once the seal has been penetrated in order to withdraw a first dose from the vial, the chamber may no longer be sterile. For example, penetrating a seal with an injection device could leave a puncture hole in the seal. Alternatively, where a self-sealing type of seal, such as a septum, is used, fragmentation problems might occur. An example of such fragmentation problems includes the dislodgement of a fragment of the septum into the chamber on insertion of the injection device.
Sterility may be maintained by the use of a component within the vial contents which may include preservatives such as thiomersal or 2-phenoxyethanol. It is preferred, however, that vaccines should be substantially free from mercurial material.
An objective of the invention is to maintain sterility in a multidose vial during and after the withdrawal of a first dose therefrom, without the use of preservatives within the vial contents.
Sterility may also be maintained by the use of a sterile withdrawal spike. Such sterile withdrawal spikes are known in the art. One example is the Mini Spike™ produced by B. Braun™. A typical example is illustrated in FIG. 2 and disclosed in U.S. 2002/0040206 (the contents of which is hereby incorporated by reference). The sterile spike 30 comprises a housing 32 and a piercing thorn 34 protruding centrally and perpendicularly from the housing. The housing 32 is plate-shaped and comprises a first filter chamber 3 containing a fluid filter 5 and a second filter chamber 7 containing an air filter 9 (see FIG. 8). The thorn 34 has a piercing tip 36. A fluid duct 11 and an air duct 13 extend in longitudinal direction through the piercing thorn 34. Said two ducts end in the conical area of the tip 36 of the piercing thorn 34. Inside the housing 32 the ducts are isolated from each other. The fluid duct 11 communicates with the fluid filter chamber 3, and the air duct 13 communicates with the air filter chamber 7. The fluid filter chamber 3 is further connected with a duct 15 which extends through a tube 38 which, in extension of the piercing thorn 34, is connected with the housing 32 and protrudes to the opposite side of the housing 32. Two wing-shaped portions 40, 42 laterally engage with the tube 38, said wing-shaped portions 40, 42 being configured as quadrantal sectors and extending between the tube 38 and the housing 32. The two wing-shaped portions 40, 42 together form a semicircle located in a plane extending at right angles to the plane of the plate-shaped housing 32. On both sides of the wing-shaped portions 40, 42 concentric ribs 44 are provided which facilitate the gripping by hand. Thus the wing-shaped portions 40, 42 form a gripping part, and the plate-shaped housing 32 forms a manually actuated impact surface when the piercing thorn 34 is inserted into a stopper, such as the cap 24 of the multidose vial 10.
In the wing-shaped portion 40 a vent hole 46 communicating with the air filter chamber 7 is provided. In the air flow path the air filter membrane 9 contained in the air filter chamber 7 is arranged between the air duct 13 and the vent hole 46. It is envisaged that a withdrawal spike for use in the present invention could omit the fluid filter membrane 9, since this could conceivably inhibit flow of component out of the vial.
At the end of the tube 38 a connecting piece 17 having an inner cone 19 and externally threaded ribs 21 of a Luer-Lock connector is arranged (see FIG. 8). Said connecting piece 17 is annularly surrounded, at a lateral distance, by a protective jacket 48. Said protective jacket 48 comprises a bottom portion 49 sealingly adjoining the base part of the connecting piece 17. The protective jacket 48 protrudes beyond the outer end of the connecting piece 17. At the edge of the pot-shaped protective jacket 48 a hinged cover 50 is fastened by a living hinge 51. Said cover 50 is further connected via a toggle joint arm 52 with the protective jacket 48. Said toggle joint arm 52 effects a snapping behaviour of the cover 50 which assumes either an open position (FIG. 8) or a closed position (FIGS. 1, 4, 5 and 7). On the inside of the cover a projecting edge 53 is arranged which, in the closed position of the cover 50, fittingly engages with the protective jacket 48. Further, a cylindrical closing part 54 (FIG. 8) is provided on the inside of the cover 50, said closing part 54 entering the inner cone of the connecting piece 17 in the closed position.
Inside the connecting piece 17 a valve 71 is arranged (see FIG. 8 in particular). Said valve 71 comprises a valve disk 73 and a valve opener 75. The edge of said valve disk 73 of elastomeric material is clamped between the edge of the tube 38 and an edge of the connecting piece 17 and is gripped over by a sleeve 23 of the connecting piece. The valve disk 73 comprises a slot or opening structure. It is of the self-closing type, i.e. without exertion of external pressure it assumes the closed position shown in the drawings.
The valve opener 75 is a tubular part containing a longitudinal duct 77 having an end pushing against the central portion of the valve disk 73. On the circumferential area of the valve opener 75, projections (not shown) protruding to the outside are arranged which are distributed over the circumference. The upper ends of said projections push against an annular shoulder 25 inside the connecting piece 17. Above the annular shoulder 25 the inner cone 19 is located.
Below the valve disk 73 a cavity 79, which is enlarged relative to the duct through the tube 38, is provided and the valve disk can move into said cavity 79 when it is deformed by the valve opener 75.
During use of the withdrawal spike 30 a male Luer cone is placed upon the connecting piece 17, or the cone 302 of a syringe 300 is inserted into the inner cone 19. During this process the penetrating part pushes against the front face of the valve opener 75 whereby the latter is displaced inside the connecting piece 17 thus pressing the valve disk 73 open. The valve 71 is thus forced to remain in the open position as long as the external part protrudes into the connecting piece 17. Thereafter the spring action of the valve disk 73 causes valve opener 75 to return into its initial position, and the valve 71 closes again.
Any fluid residues in the connecting piece 17 or in the valve 71 are prevented from flowing out by closing the cover 50.
It will be appreciated that the above description of the sterile withdrawal spike is purely by way of example, and that any suitable sterile withdrawal spike may be used in conjunction with the invention. In particular, it is possible to omit the internal valve 71.
A drawback of inserting such a withdrawal spike 30 into a multidose vial 10 is that the spike 30 is not secured to the vial 10 other than by frictional forces between the thorn 34 and the cap 24. The spike 30 is therefore liable to be displaced from and within the vial 10. Possible displacements include: an axial displacement, wherein the thorn 34 is displaced axially relative to the cap 24; and/or an orientational displacement (or a wobble), wherein the longitudinal axis of the thorn 34 becomes non-parallel with a longitudinal axis of the vial 10. This has potentially serious consequences. In a worst case, the spike may be displaced to such an extent that the thorn 34 is completely dislodged from the puncture hole that it has created in the cap 24. The vial 10 would then have to be discarded without further use, i.e. wasting any remaining doses, because of the risk of lack of sterility due to the exposed puncture hole and/or to the need to insert another withdrawal spike 30.
Even if the thorn 34 were not completely dislodged, any displacement thereof from an ideal predetermined position within the vial 10 could have serious consequences. The ideal position of the thorn 34 with respect to the vial 10 locates the thorn tip 36 at a predetermined depth within the vial chamber 20. The predetermined depth is selected so that the thorn tip 36 is inserted beyond the cap 24 so that the two ducts in the conical area of the tip 36 are not blocked at all by the cap 24, which could hinder withdrawal of the vial contents.
Another consideration is to minimise wastage of the vial contents. Typically, the vial contents are withdrawn by inverting the assembled vial 10 and spike 30 so that gravity urges the contents towards the vial cap 24, whence the contents can be withdrawn via the thorn 34, specifically via the fluid duct thereof and its opening in the thorn tip 36. With the assembly inverted, any contents lying between the cap 24 and the fluid duct opening in the thorn tip 36 are inaccessible and hence cannot be withdrawn. Accordingly, if the thorn tip 36 were to be inserted beyond the depth necessary for its ducts to be clear of the cap 24, then the volume of inaccessible contents would increase.
Yet another consideration is to ensure central penetration of the cap 24 by the piercing tip 36 of the thorn 34. If the penetration were to be significantly off-centre, there is a risk that the duct openings in the tip 36 could become at least partially blocked by the interior wall of the vial neck portion 16.
It is therefore desirable to ensure that the spike 34 is inserted to the correct predetermined depth within the vial 10, and at the right location and orientation. This might be accomplished by skilful manipulation by a user. For example, a skilled practitioner might be able to insert the spike 34 to the correct depth and at the right location and orientation. However, this approach is liable to human error and a consistent insertion could not be ensured.
It is also desirable to secure the spike 30 to the vial 10 to eliminate the displacement issues noted above. Again, this might be accomplished by a skilled practitioner who might be able to hold the spike 30 to the vial 10 to prevent their relative displacement. However, this approach is again liable to human error and further might require the use of both hands and/or awkward manipulation. A more user-friendly, less fatiguing approach is therefore desirable.
An ancillary problem associated with known withdrawal spikes 30 such as that described above relates to the valve 71 within. With the valves that are typically used, it is possible for fluid residues to become trapped in the valve, where bacteria could collect and hence pose a contamination risk to subsequent fluid withdrawals through the spike 30. In particular, fluid residues may be trapped in difficult to access areas within the valve, particularly in the area above the valve disk 73, such as in the recess between the inner cone 19 and the top of the valve opener 75.
Swabbable valves, which present a flush upper surface when in a sealed, closed position for easy swabbing, e.g. by disinfectant, are known. One known manufacturer of such valves is Halkey-Roberts.
It is therefore envisaged that spikes 30 for use in connection with this invention could be provided with such a swabbable valve. In particular, a swabbable valve could be housed within the connecting piece 17 so as to present an upper surface that, when in the closed position, is flush with the upper surface of the connecting piece. With such an arrangement, the problematic recess between the inner cone 19 and the top of the valve opener 75 would be removed. Indeed, it is envisaged that withdrawal spikes could, in general and independently of any association with an adapter, be provided with swabbable valves to benefit from the advantages associated therewith of eliminating areas within which bacteria can collect.
As indicated above, one possible application of the invention is for a pandemic influenza vaccination programme. Influenza vaccines are described in more detail in chapters 17 & 18 of Vaccines. (eds. Plotkin & Orenstein). 4th edition, 2004, ISBN: 0-7216-9688-0.
It is an object of the invention to provide further and improved methods and devices for delivering vaccines, and in particular to increase the safety thereof.